• The Aminopenicillins:  Ampicillin and Amoxicillin

  • Some Therapeutic Uses

    • Meningitis and CNS Infections

      Meningitis Audio Overview

      •  

        Meninges of the CNS

        Meninges diagram Attribution SVG by Mysid, original by SEER Development Team [1], Jmarchn, CC BY-SA 3.0 <https://creativecommons.org/licenses/by-sa/3.0>, via Wikimedia Commons https://commons.wikimedia.org/wiki/File:Meninges-en.svg

      •  

        Neisseria meningitidis

        "This micrograph depicts the presence of aerobic Gram-negative Neisseria meningitidis diplococcal bacteria; Mag. 1150X. Meningococcal disease is an infection caused by the bacterium called N. meningitidis or meningococcus. The meningococcus lives in the throat of 5-10% of healthy people. Rarely, it can cause serious illness such as meningitis or blood infection." Attribution SDr. Brodsky, Public domain, via Wikimedia Commons https://commons.wikimedia.org/wiki/File:Neisseria_meningitidis.jpg

       

      • Ampicillin is an important antibiotic in the treatment of certain forms of bacterial meningitis.

        • While third-generation cephalosporins (e.g. ceftriaxone or cefotaxime) are the mainstay for most community-acquired bacterial meningitis (covering S. pneumoniae, N. meningitidis), there is one prominent pathogen that cephalosporins do not cover: Listeria monocytogenes.³ 

          • Listeria primarily causes meningitis in neonates, the elderly (>50 years), pregnant women, and immunocompromised hosts, and it is intrinsically resistant to cephalosporins.2

          • Ampicillin (or penicillin G) is the drug of choice for Listeria infections, including meningitis.²

          •  WHO guidelines for bacterial meningitis recommend adding ampicillin to the empiric regimen whenever Listeria is a consideration.⁴    Often an aminoglycoside (gentamicin) is added to ampicillin for Listeria meningitis in severe cases to achieve synergy, though definitive evidence of improved outcomes with gentamicin is limited.²   Gentamicin is often part of initial therapy (along with e.g. ampicillin) for Listeria.²

          • An alternative for Listeria coverage, for example in the presence of penicillin allergy, is trimethoprim-sulfamethoxazole, as it penetrates the CSF and is listericidal. 

            • Meropenem is another alternative.²

        • Aside from Listeria, ampicillin is active against many other meningeal pathogens.

          • Ampicillin covers Group B Streptococcus (Streptococcus agalactiae), a cause of neonatal meningitis, and is often included (with gentamicin) in empiric neonatal meningitis regimens.⁵ 

            • It also covers Neisseria meningitidis, Escherichia coli, non-beta-lactamase H. influenzae.

              • Penicillin or ampicillin can be used to treat susceptible N. meningitidis meningitis.

            • Ampicillin’s ability to penetrate the CSF is good when the meninges are inflamed⁵, achieving bactericidal concentrations.

              • Because up to ~30% of H. influenzae strains produce beta-lactamase and because penicillin-resistant pneumococci exist, the standard of care in meningitis is to use ceftriaxone (which covers those) plus vancomycin (for resistant pneumococci), and add ampicillin specifically for Listeria coverage when indicated.²

              • In summary, ampicillin is indispensable for Listeria meningitis and would be included in empiric therapy for meningitis in neonates and older adults.²

                • Ampicillin penetrates well into brain abscesses and cerebrospinal fluid with inflammation, so it may be used for Listeria brain abscess.⁶ 

    • Endocarditis and Enterococcal Infections

      • Enterococcus (E. Faecalis & E. Faecium)

        Attribution Enterococcus (E. Faecalis & E. Faecium) Dirty Medicine Decaember 28, 2021. https://www.youtube.com/watch?v=DliOv1GXDdE https://www.youtube.com/@DirtyMedicine

      • Ampicillin is useful in treating enterococcal infections, including endocarditis and enterococcal bacteremia.^8,9 

        • Enterococcus faecalis is a Gram-positive coccus inherently resistant to many antibiotics, but it is usually susceptible to ampicillin, unlike E. faecium, which is often ampicillin-resistant.^6,7 

          • Enterococcus faecalis

            Attribution United States Department of Agriculture, Public domain, via Wikimedia Commons 2 September 2009. https://commons.wikimedia.org/wiki/File:Enterococcus_faecalis20023-300.jpg

      • Ampicillin is may be bacteriostatic by itself against enterococci in vitro , meaning it inhibits growth but often does not rapidly kill the organisms.¹⁰ 

        • Serious enterococcal infections like endocarditis (infection of heart valves), bacteriostatic activity is not sufficient thus necessitating bactericidal combinations.

          • Standard therapy for Enterococcus faecalis endocarditis is ampicillin combined with an aminoglycoside (gentamicin) or cephalosporin (ceftriaxone) to achieve bactericidal synergy.¹¹ 

            • Ampicillin damages the cell wall and may facilitate gentamicin entry into the bacterial cell, together proeducing a bactericidal effect.¹² 

          • Clinical guidelines (American Heart Association and IDSA) traditionally recommended ampicillin (or aqueous penicillin G) plus gentamicin for enterococcal endocarditis for 4–6 weeks.¹³

            • This regimen cures most E. faecalis endocarditis, but gentamicin can cause nephrotoxicity and ototoxicity, and some enterococcal strains have high-level aminoglycoside resistance (HLAR).

          • Other current clinical guidelines suggest combining ampicillin with other agents e.g. ceftriaxone or daptomycin etc.¹⁴

      • Enterococcal bacteremia management begins with identifying and controlling the source, which is most often the urinary tract, an intra-abdominal process, or an infected intravascular catheter.¹⁵

        • For ampicillin-susceptible strains, high-dose IV ampicillin is a treatment of choice.¹⁶ 

          • A critical step in management is to rule out endocarditis, particularly in cases of E. faecalis bacteremia, which often requires echocardiography.17

          • For uncomplicated bacteremia where the source is controlled (e.g., catheter removal), a treatment duration of 7 to 14 days is generally sufficient.¹⁸

  • Some Adverse Reactions

    • Allergic reactions

      • Amoxicillin and ampicillin can cause hypersensitivity reactions in susceptible individuals.

        • These reacttopms range from mild rashes to severe anaphylaxis.

          • Penicillin allergy is the most important contraindication,

            • Any patient with a history of penicillin anaphylaxis should not receive aminopenicillins, due to risk of IgE-mediated reaction.¹⁹  Typical allergic manifestations include urticaria (hives), angioedema, pruritus, and wheezing or anaphylactic shock in severe cases.¹⁹ 

              • Aminopenicillins can also cause delayed hypersensitivity rashes that are not IgE-mediated.²⁰

                • An example is ampicillin/amoxicillin rash in patients with viral infections: when ampicillin or amoxicillin is administered during acute Epstein-Barr virus (mononucleosis) infection, a high proportion of patients develop a non-allergic generalized maculopapular rash.²¹

                  • A case report suggests that aminopenicillins may trigger characteristic rashes after the onset of mononucleosis, even when given during the infections latent phase.²² 

                • This “ampicillin rash” is immunologically distinct from a true penicillin allergy and does not preclude future use of penicillins, but it is a well-known reaction.²³

                • Amoxicillin/ampicillin are generally avoided in patients with mononucleosis as these drugs may induce a pruritic erythematous maculopapular skin rash.²⁴ 

      • Gastrointestinal Effects

        • Aminopenicillins are associated with GI side effects.

          • Adverse effects include diarrhea, nausea, and vomiting.

            • Ampicillin frequently causes diarrhea when given orally.²⁵

              • Amoxicillin and ampicillin can cause changes in the gut microbiome that lead to superinfections: for instance, overgrowth of Candida yeasts (oral thrush or vaginal yeast infection) or Clostridioides difficile colitis.²⁶ 

              • Antibiotic-associated diarrhea can occur with aminopenicillins, and in some cases severe C. difficile–associated diarrhea (pseudomembranous colitis) has been reported.^19,26

September, 2025